Isoquinolyl heterocyclic ethers



Patented June 2, 1953 ISOQUINOLYL HETEROCYCLIC ETHERS James W. WilsonIII and Glenn E. Ullyot, Philadelphia, Pa.,

assignors to Smith, Kline &

French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Application November 10, 1950, Serial No. 195,122

6 Claims. (01. 260-286) This invention relates to certain new chemical compounds, more particularly to certain heterocyclic ether derivatives of isoquinoline which possess physiological properties and, more particularly, are adapted for use as local anesthetic agents.

From the broad standpoint, the chemical compounds contemplated by this invention will have the following structure:

in which:

Y is selected. from the group consisting of substituted and unsubstituted heterocyclic radicals of not more than 2 fused rings, the hetero atoms of which are nitrogen atoms, and the substituents of which may be lower alkyl, lower alkoxy, and phenol-loWer-alkyl groups;

R is selected from the group consisting of hydrogen, lower alkyl and benzyl groups; and

R and R are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, amino, lower alkylamino and lower acylamino.

More specifically, the compounds contemplated by this invention will have the following structure:

in which:

Y is selected from the group consisting ofsub stituted and unsubstituted heterocyclic radicals of not more than 2 fused rings, the hetero atoms of which are nitrogen atoms, and the substituents of which may be alkyl not in excess of 4 carbon atoms, alkoxy not in excess of 4 carbon atoms, and benzyl groups;

R. is selected from the group consisting of hydrogen, lower alkyl and benryl radicals; and

R and R are selected from the group consisting of hydrogen, alkyl not in excess of 4 carbon atoms, alkoxy not in excess of 4 carbon atoms, amino, alkylamino of not more than 4 carbon atoms, and acylamino of not more than 4 carbon atoms.

This invention also contemplates the organic and inorganic salts of the above compounds.

It will be appreciated from the above definition that the compounds contemplated by this invention include the aminoalkoxyisoquinoline derivatives defined. above and their organic and inorganic acid salts, which latter will be readily prepared from the. former by methods well known to the art using, for example, but not by way of limitation, phosphoric, hydrochloric, hydrobromic, sulfuric,-succinic, benzoic, tartaric acids, and the like.

As has been indicated, the salts contemplated by this invention will be prepared from the free bases, for example, by mixing the free bases, which are variously oils, liquids or solids, depending upon the nature of the groups attached to the isoquinoline nucleus, with the organic or inorganic acid desired to be used, either directly or in the presence of a suitable solvent, such as alcohol, water, ether, benzene, or the like. Variously the salt will precipitate directly and can be collected on a filter. In other instances, it will be necessary to remove the solvent by distillation and drythe salts produced by warming in vacuo.

Generally speaking, where the compounds in accordance with this invention are used as therapeutic agents, the salts will be preferred for such use.

The starting materials required for the preparation of the compounds in accordance with this invention as defined above are known to the art or may be readily prepared by known methods.

More particularly the starting materials consist of isoquinoline derivatives represented by the formulae:

wherein R and R are as defined above, and heterocyclic alcohols represented by the formula YOH wherein Y is as defined above.

The required isoquinoline derivatives as illustrated by the above formulae may, for example, be prepared according to the methods described in the literature, as, for example, Gabriel and Colman, Ben, 33, 905 (1900), and Gabriel and Newman, Ben, 25, 3569 (1892) and as described in applications for United States patents heretofore filed by Glenn E. Ullyot, i. e., serial No. 116,866, and Serial No. 116,868, now Patent No. 2,538,342, issued Jan. 16, 1951. The amino alcohols required are well known or the preparation of any particular alcohol required by well known methods will be obvious to those skilled in the art.

Generally speaking, the compounds in accord- 3 ance with this invention will be prepared by treating the isoquinoline derivatives defined above with, for example, an excess of phosphorus oxychloride to produce the corresponding 1- chloroisoquinoline derivatives as indicated in the general reaction below:

This reaction will, for example, be effected by placing the isoquinoline derivatives in a suitable flask, adding one to three molar equivalents of phosphorus oxychloride and heating under a reflux condenser until the evolution of hydrogen chloride ceases. The excess phosphorus oxychloride is then removed by distillation and the product purified by crystallization or distillation in vacuo, or, alternatively the reaction mixture may be poured into ice water, the mixture neutralized by the addition of alkali and the product isolated by extraction with a solvent, drying and distillation. If desired, this reaction may be carriedout in the presence of a solvent, such as benzene, toluene, or the like.

By Way of further illustration, the l-chloroisoquinoline compounds used as starting materials will be prepared from the corresponding isocarbostyrils by the action of phosphorus oxychloride, by the general method, of, for example, Gabriel and Colman, referred to above. By way of example, 56 g. of B-n-butylisocarbostyril in 86 g. of phosphorus oxychloride is refluxed for 16 hours, cooled and poured into 300 g. of cracked ice. The cold solution is carefully neutralized with sodium hydroxide and the product is extracted with ether. After drying over anhydrous sodium sulfate the ether is removed and the product distilled. This product will boil at 155-158/6' mm. pressure. The several other isoquinoline compounds will be made in an exactly analogous manner.

As further illustrative, the following l-chloroisoquinoline compounds may be mentioned:

1-chloro-3-benzylisoquinoline; B. P. 180-182/0.5'

1 chloro amino 3 ethylisoquinoline;

M. P. 124-125 C.

1-chloro-6,7-dimethoxyisoquinoline; (picrate derivative) M. P. 190-191 C.

The preparation of nuclear l-chloroisoquinoline intermediates will be illustrated and made clear by the following example:

One hundred grams of 6,7-dimethoxy-3-ethylisocarbostyril is dissolved in 190 g. of phosphorus oxychloride and refluxed for 18 hours. The solution is cooled and poured into cracked ice.

After neutralization of the decomposed reaction mixture with potassium hydroxide, the product, 1 chloro 6,7 dimethoxy 3 ethylisoquinoline, is isolated by ether extraction in the usual manner.

i The l-chloroisoquinolinederivatives as defined above having been obtained as described above, the amino alcohol YOH required for the particular compound in accordance with this invention desired to be produced, where Y is given above, dissolved in a suitable solvent such as benzene, toluene, xylene, or the like, is converted into an alkali metal derivative by treatment with a finely divided alkali metal, as, for example, sodium, potassium or lithium, or the like. The l-chloroisoquinoline derivative prepared as above is added to the resulting suspension or solution of alkali metal derivative of the heterocyclic alcohol. The l-chloroisoquinoline derivative may be added as a solution in the same solvent as is used to prepare the alkali metal derivative, if deisred.

Theaddition of the l-chlorisoquinoline' derivative is made rapidly or is carried out with stirring and over a period of time suitable for the control of the reaction mixture.

Following the addition of the l-chloroisoquinoline derivative, the mixture is stirred and heated at a suitable temperature up to the boiling point of the solvent. During the reaction a metal chloride precipitates. On completion of the reaction, the reaction mixture is cooled and filtered to remove the precipitated metal chloride, or this may be removed by washing. The solvent is then removed by distillation and the isoquinoline de rivative, final product, is purified by distillation in vacuo. Desired purification may be effected by dissolving the reaction product in a suitable solvent, such as dry benzene or dry ether and treating the solution with anhydrous hydrogen chloride. The resulting salt of the product which precipitates may then be collected and crystallized from a suitable solvent.

As more specifically illustrative of the preparation of the compounds contemplated by this invention, the following specific examples of the preparation of specific compounds contemplated by this invention will serve to exemplify the preparation of all the several compounds, since all of the several compounds contemplated will be prepared in the same manner with the selection of starting materials required for the production of any particular desired specific compound.

Example 1 1-[4' (1 methylpiperidyloxy)l 3 ethylisoquinoline:

CED-CH2 N-CH3 GHQ-CHI A mixture of 2.3 g. of sodium and 14 g. of 1- methyl-l-piperidinol in 175 cc. of dry toluene was heated at gentle reflux with efficient stirring for four ,hours. When all the sodium had disappeared, the mixture was cooled to 35 C., 19.2 g. of 1-chloro-3-ethylisoquinoline was added, and the mixture was again heated to gentle reflux with stirring for three and one-half hours. It was then cooled and extracted with two 100 cc. portions of water and then with four cc. portions of approximately 2N hydrochloric acid.

,5 The acid solution was made basic with 40%- sodium hydroxide solution. The oil which .sepa rated was taken into ether by four extractions. The ether solution, after washing with water, was dried over anhydrous potassium carbonate. The potassium carbonate was removed by filtration and the other by evaporation in vacuo. The residual orange oil was vacuum distilled to yield a yellow oil; B. P. 191-I92-f5 mm. Redistillation gave a product which has a B. of 184-18574 mm.

Example 2' 1 [4' (1-methylpiperidyloxy)] 3 butylisoquinoline succin'ate:

CEz'--'CH CHi' G' a To 1.4 g. of sodium sand suspended ih-150 cc. of warm, dry xylene was added" 6.9g. of l-methyll-piperidinol. The reaction mixture was stirred vigorously while heated at 120-130 C. until all of the sodium had reacted: (about 3 hours). The solution was then cooled to (SO-70 C. and 11.0 g. of. 1-chloro -3' butylisoduinolinewas added all at once. below the reflux temperature for ten hours when it was cooled to 30 C. and extracted with three 100 cc. portions of hydrochloric acid. The acidic extractions were then made strongly alkaline with 4.0% sodium hydroxide and the yellow oil which separated was taken into ether by means of three '75 cc. portions. After drying the ether solution (MgSOii), the solvent was removed by distillation under reduced pressure and the residual orange oil distilled in vacuo, to yield a product of B. P. 168-170/1 mm., n 1451546.

To 1.00 g. of the free base .so prepared, dis-- solved in 10 cc. of #30 alcohol, was: added 0.39 g. of succinic acid. The mixture was warmed slightly to bring the acid into solution and then the alcohol was removed by distillation under reduced pressure toleave a viscous slightly yellow oil which solidifiedv when scratched with a glass rod. The. product was recrystallized from From 15.2 g. of 1,2,6-trimethylpiperidinol-4 hydrochloride was obtained 9.9 g. of theiree base. This was accomplished by dissolving the salt: in a minimum amount of water and; then making the solution strongly alkaline with io a-sodium hydroxide. The solution was thenextracted with six 25 cc. portions of ether. The ether solution was dried (MgSOQ- and the ether removed by distillation under reduced pressure. The residual oil was distilled in: vacuotoqgive: the tree base as a colorless oil, B. PJB -"Mf/J. 1.45170;

The reaction mixture was stirred just 6. T0019 g. of sodium sand suspended in 150 cc. of dry xylene was added 5.7 g. of 1,2, 6 trirnethylp'iperidinohe and the resulting mixture stirred at 130-140" C. for two hours when an additional 1.5 g. of the base was added. The mixture was cooled to (SO-65 C. and 6.6 g. of l-chlord-B-bu tylisoquinoline was added all at once. The reaction mixture was stirred at 135-1 4='0 C. for ten hours, cooled to C. and extracted with three cc. portions of 10% hydrochloric acid. The acidic extractions were made" strongly alkaline with 'i0% sodium hydroxide and the orange oil which separated was taken into other by means of four 25 cc. portions The ether solution was washed with two 50 cc. portions or partially saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the ether removed by distillation under reduced pressure.

The residual oil was distilled in vacuo to give" a viscous yellow oil. 13'. P. 174-17671 mm, n 1.5492.

Example 4 I 1-tropyloxy f-ethylisoquinoline:

CHr-CHCH2 o-r zn NCHa tional 1-2 g. of tropine was added. When all;

of the sodium had reacted, the solution was cooled to -70 and 9.6 g. of l-chloro 3-ethyl-isoquinoline was added all at once. The reaction mixture was stirred just below the reflux temperature for 13 hourswhen itwas cooled to 25 C. and extracted with three cc. portions of dilute hydrochloric acid (10%). The acidic extractions were made strongly basic with 40% sodium hydroxide and the yellow oil which separated was taken into ether by means offour 50 cc. portions. The ether was dried with anhydrous MgSOr and the solvent removed by distillation under reduced pressure. The residual oil was distilled in vacuo to give a viscous yellow oil, B. P. 177-1'78 /1 mm., 15 1.5778.

Example- 5 1-tropyloxy-3-n-butylisoquinoline monohydrochloride:

ni=on om 7. of concentrated hydrochloric acid. The mixture was diluted to 15 ccQwith acetone and placed in the deep freeze. After two weeks the crystalline white solid which had formed was separated by filtration, washed with small portions of acetone and dried to constant weight to give l-tropyloxy- 3-n-butylisoquinoline monohydrochloride having a melting point of 238-239".

Example 6 1-'(4'-piperidy1oxy) -3-ethylisoquinoline:

CH2CH2 oc NH This compound was prepared in a manner identical with that described for the preparation of Example 1, with the exception that an equimolar amount of 4-piperidin0l was utilized in place of 1-methyl-4-piperidinol as a starting material to react with the 1-chloro-3-ethylisoquinoline.

Example 7 1-[4-(1-n-propy1piperidyloxy)l 3 butylisoquinoline:

CHrCHz N-CHzCHzCHa CHr-C 2 This compound was prepared in a manner identical with that described for the preparation of Example 2, with the exception that an equimolar amount of 1-n-pr0py1-4-piperidin01 was utilized in place of 1-methyl-4-piperidinol as a starting material to react with the l-chloro-B-butylisoquinoline. The product was obtained as a yellow oil; B. P. 199-201/1 mm., n 1.5456.

Example 8 1 [3 (1 methylpiperidyloxy) l-3-buty1isoquinoline CH2CH2 CH2N This compound was prepared in a manner identical with that described for the preparation of Example 2, with the exception that an equimolar amount of l-methyl-3-piperidinol was utilized in place of l-methyll-piperidinol as a starting material to react with the 1-chloro-3- butylisoquinoline. The product was obtained as a yellow oil; B. P. 170-1'71 C./0.4 mm.

Example 9 1 [4' (1 methylpiperidyloxy)l-3-ethyl-5- aminoisoquinoline:

CHr-CH:

CHa CHz-CHa This compound was prepared in a manner identical with that described for the preparation of Example 1, with the exception that an equimolar amount of 1-chloro-3-ethyl-5-aminoisoquinoline was utilized in place of 1-chloro-3- ethylisoquinoline as a starting material to react with the sodium salt of 1-methyl-4-piperidino1.

Example 10 1 [4' (1 methylpiperidyloxy)l-3-ethyl-5- acetylaminoisoquinoline:

This compound was prepared by reacting the product of Example 9 with acetic anhydride to form the acetylamino product.

Example 11 1 [4 (1 methylpiperidyloxy)l-3-ethyl-5- n-propylaminoisoquinolinez This compound was prepared in a manner identical with that described for the preparation of Example 1, except that 3-ethyl-5-n-propylamino-1,2-dihydroisoquinolone-1 was utilized as a starting material and converted to the l-chloro derivative to react with the sodium salt of 1- methyl-4-piperidino1. The 3-ethyl-5-n-propylamino-1,2-dihydroisoquinolone-l was prepared using well known alkylation techniques by treating the 5-amino compound with n-propyl iodide in the presence of excess sodium bicarbonate.

Example 12 1 [4' (1 methylpiperidyloxy)l-3-ethy1-5- diethylaminoisoquinoline:

CHPCHQ N-CH;

CHz-CHs O-CH Example 13 1 [4' (1 imethylpiper'idyloxy) l-7-n-butylisoquinoline:

, CHr-C H2 o-c NCHa This compound was prepared in a manner identical with that described for the preparation of Example 1, with the exception that an equimolar amount of 1-chloro-'7-ethylisoquinoline was utilized in place of l-chloro-3-ethylisoquinoline as a starting material to react with the sodium salt of l-methyl-4-piperidinol.

Example 1 [4 (1 methylpiperidyloxy)l 6,7 dimethoxyisoquinoline:

OH2CH2 ?-C N-CHa CH2-CHI 01130- N This compound was prepared in a manner identical with that described for the preparation of Example 1, with the exception that an equimolar amount of 1-chloro-6,7-dimethoxyisoquinoline was utilized in place of 1-chloro-3- ethylisoquinoline as a starting material to react with the sodium salt of l-methyll-piperidinol.

Example 16 1 (1 methylpiperidyloxyH 3 benzylisoquinoline:

GHQ-CH2 N-CH CHrOn This compound was prepared in a manner identical with that described for the preparation of Example 1, with the exception that an equimolar amount of 1-chloro-3-benzylisoquinoline was utilized in place of l-ohloro-S-ethylisoquinoline as a starting material to react with the sodium salt of l-methyll-piperidinol.

Example 17 1 [4' (-1 benzylpiperidyloxyH 3 butylisoquinoline monohydrochloride:

To 0.85 g. of sodium sand suspended in 150 cc. of dry xylene was added 7.7 g. of 1-benzyl-4- piperidinol and the resulting mixture stirred just below the reflux temperature for five hours. The pale yellow solution was cooled to 60 and 7.7 g. of 1-chloro-3-butylisoquinoline was added all at once. The reaction mixture was stirred at for eight hours when it was cooled to 25 C. and extracted. with four 50 cc. portions of dilute hydrochloric acid. The acidic extractions were cooled to 0 0., made strongly alkaline with 40% sodium hydroxide, and the yellow oil which had separated was taken into ether by means of four '75 cc. portions. The ether solution was dried (MgSO4) and the solvent removed under reduced pressure. The residual orange oil was distilled in vacuo to give a viscous yellow oil, B. P. 237- 240/0.4 mm., n 1.5801.

The monohydrochloride salt was prepared by adding "0.5 g. of the above free base to 25 cc. of water containing one equivalent of hydrochloric acid. The solid which formed immediately was removed by filtration, Washed with small portions of cold water and recrystallized from water to give 1 [4 (l benzylpiperidyloxyH 3 butylisoqui-noline monohydrochloride as fine white needles M. P. 203-204 C.

It will be understood that the various particular starting materials requisite for the preparation of the various compounds contemplated by this invention are known, or, as has been clearly pointed out, they may be readily prepared by known procedure. The several compounds contemplated by this invention will be prepared from starting materials indicated by the procedure generally outlined and specifically amplified above, all of which will be apparent to those skilled in the art.

What is claimed is:

1. Chemical compounds selected from the class consisting of the free base and its acid addition salts, the free base having the formula:

in which Y is a heterocyclic radical selected from the group consisting of tropyl, piperidyl, piperidyl substituted by an alkyl radical having not in excess of 4 carbon atoms, and piperidyl substituted by a benzyl radical; R is selected from the group consisting of hydrogen, lower alkyl and benzyl radicals; and R and R are selected from the group consisting of hydrogen, alkyl having not in excess of 4 carbon atoms, alkoxy having not in excess of 4 carbons atoms, amino, alkylamino having not in excess of 4 carbon atoms, and acylamino radicals having not in excess of 4 carbon atoms.

11 2. A compound having the structure:

CH2OH2 -0\ N-OH:

CgH

3. A compound having the structure:

CH:- H

0-0 N-CH:

CHg

4. A compound having the structure:

CH:CH-CH: O(IJH ITC Hz 1113- H-CH1 5. A compound having the structure:

CHz()H-CHI 6. A compound having the structure:

CHE-CH2 (|)C CH1 \q CHrN 15 JAMES W. WILSON III. GLENN E. ULLYO'I.

No references cited. 

1. CHEMICAL COMPOUNDS SELECTED FROM THE CLASS CONSISTING OF THE FREE BASE AND ITS ACID ADDITION SALTS, THE FREE BASE HAVING THE FORMULA: 